Transforming growth factor-beta 1 and its receptors in human lung cancer and mouse lung carcinogenesis

The transforming growth factor-betas (TGF-betas) are multifunctional protei ns that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-beta type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-beta is thought to contri bute to the development of many types of tumors. In the present study, we h ave examined expression of the proteins and mRNAs for TGF-beta1, TGF-beta R I, and TGF-beta RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens. Immunohistoch emical staining for TGF-beta1, TGF-beta RI, and TGF-beta RII using specific antibodies in normal human lung showed expression of the 3 proteins in the epithelium of bronchi and bronchioles as well as in alveoli. Differential expression of TGF-beta RI and TGF-beta RII proteins was detected in 5 NSCLC cell lines using Western blot analysis, with reduced levels in 3 cell line s. A panel of 45 formalin-fixed and paraffin-embedded NSCLC specimens showe d positive immunostaining for TGF-beta1, TGF-beta RI, and TGF-beta RII, wit h reduced TGF-beta RII in poorly differentiated adenocarcinomas and squamou s cell carcinomas and some moderately differentiated adenocarcinomas. In si tu hybridization studies conducted with specific riboprobes for TGF-beta1, TGF-beta RI, and TGF-beta RII showed corresponding localization of expressi on of the mRNAs in the specimens that showed positive immunostaining for th e proteins. To investigate the roles of TGF-beta1, TGF-beta RI, and TGF-bet a RII in chemically induced mouse lung tumorigenesis, we examined the expre ssion of their proteins and mRNAs in 2 mouse model systems. Whereas express ion of the proteins and mRNAs for TGF-beta1 and TGF-beta RI was comparable in lung adenomas and bronchioles of A/J mice treated with benzo(alpha )pyre ne, decreased immunostaining and hybridization for TGF-beta RII protein and mRNA was detected in 50% of lung adenomas in these mice. Interestingly, ex pression of TGF-beta1 and the TGF-beta receptor proteins was similar to tha t of bronchioles in C57B1/6 mice and their littermates heterozygous for del etion of the TGF-beta1 gene treated with diethylnitrosamine. These data sho w that reduced levels of expression of TGF-beta RII occur in some, but not all, human and mouse lung tumors. This suggests that different mechanisms o f action, some of which may involve the TGF-beta signaling pathway, may con tribute to the progression of lung tumorigenesis.